Genomic Approaches to Aneuploidy

非整倍体的基因组方法

基本信息

批准号：
9902474
负责人：
Roger H Reeves
金额：
$ 59.52万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902474
关键词：
Acute Adult Adverse drug effect Affect Agonist Anatomy Aneuploidy Animal Model Animals Area Award Behavior Behavioral Model Biological Assay Birth Brain Brain region Candidate Disease Gene Cell Line Cells Cerebellum Child Chromosome 21 Clinic Clinical Clinical Trials Cognition Complementary DNA Congenital cerebellar hypoplasia Data Defect Development Dose Down Syndrome Doxycycline Drug Delivery Systems Drug Targeting Dysmorphology Electrophysiology (science)Embryo Equilibrium Erinaceidae Evaluation Exhibits Exposure to GABA Antagonists GABA-A Receptor Generations Genes Genetic Models Genomic approach Grant Growth Growth Factor Growth and Development function Hand Hippocampus (Brain)Human Chromosomes Individual Injections Intellectual functioning disability Intervention Investigation Knock-out Learning Life Luciferases Mammals Measures Mediating Memory Methods Milk Modeling Molecular Morphology Mus National Institute of Child Health and Human Development Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase Physiology Placenta Problem Solving Prosencephalon Purkinje Cells Rattus Reporter Research Rewards Rodent Model SHH gene Skeleton Societies Sonic Hedgehog Pathway Specificity Structural defect Suggestion Synaptic plasticity Testing Time Transgenes Translating Trisomy Work Zebrafish antenatal base behavior test behavioral pharmacology behavioral study biological systems calmodulin-dependent protein kinase II cognitive function combinatorial craniofacial cranium druggable target experimental study genetic approach granule cell improved in vivo morris water maze mouse Ts65Dn mouse model promoter public health relevance pup rat genome response restoration restraint side effect smoothened signaling pathway young adult

项目摘要

DESCRIPTION (provided by applicant) Down syndrome (DS), caused by trisomy for human chromosome 21 (Hsa21), is the most common genetically defined cause of intellectual disability. Structural abnormalities that are thought to contribute to learning problems are seen in the cerebellum and hippocampus of people with the condition. Treatments to correct these parts of the brain would tangibly improve the lives of children and young adults with DS and would allow them to better integrate into society. Relevance to NICHD: We recently showed that that a single injection on the day of birth of Sonic Hedgehog (Shh) pathway agonist, SAG, permanently normalizes the size and gross anatomy of the cerebellum, leads to better adult spatial problem solving, and restores electrophysiological correlates of learning in the CA1- hippocampal subfield of the Ts65Dn mouse model of DS. A number of questions remain before this finding can be translated to therapy for people. We will determine how region-specific expression of Shh in the Ts65Dn brain affects hippocampal function using a conditional "temporal-spatial" genetics approach. This will allow us to increase Shh expression around the time of birth only within the Purkinje cells of the cerebellum, or within the hippocampus, to determine where Shh stimulation is necessary and/or sufficient to correct the behavior and physiology of adult Ts65Dn mice in hippocampal tests (Specific Aim 1). Another restraint on advancing Shh treatments to the clinic is the very wide range of effects of this potent growth factor, making systemic application in people problematic. A more confined method of drug delivery might limit side effects. Another approach is to understand which Hsa21 genes act to down-regulate the Shh pathway response in cerebellum, which might suggest more "druggable" targets. We identified several candidate genes in a screen of over 100 Hsa21 cDNAs in two Shh reporter cell lines and in zebrafish embryos. Genes that significantly decrease Shh pathway activation in the LIGHT2 assay will be evaluated in additional Shh-sensitive assays to assure that they generalize across different biological systems and their specificity determined using genetic models (Specific Aim 2). Finally, Davisson's Ts65Dn mouse transformed research in DS but after 20 years, limitations in this and in fact in all mouse models have emerged. We will open a new era of investigation with a better model for behavioral and pharmacological testing by making a rat with a stably integrated copy of Hsa21 (Specific Aim 3).

描述（由申请人提供）唐氏综合症（DS）是由人类染色体第21染色体（HSA21）引起的，是最常见的智障原因。被认为有助于学习问题的结构异常在有这种疾病的人的小脑和海马中可以看到。纠正大脑这些部分的治疗方法将有明显地改善DS儿童和年轻人的生活，并可以使他们更好地融入社会。 Relevance to NICHD: We recently showed that a single injection on the day of birth of Sonic Hedgehog (Shh) pathway agonist, SAG, permanently normalizes the size and gross anatomy of the cerebellum, leads to better adult spatial problem solving, and restores electrophysiological correlates of learning in the CA1- hippocampal subfield of the Ts65Dn mouse model of DS.在这一发现之前，仍有许多问题可以将其转化为人们的治疗。我们将使用条件“颞空间”遗传学方法来确定TS65DN脑中SHH的特异性表达如何影响海马功能。这将使我们只能在小脑的浦肯野细胞内或海马内增加出生时增加SHH表达，以确定在海马测试中需要纠正成年TS65DN小鼠的行为和生理的SHH刺激的位置和/或足以纠正（特定目标1）。将SHH治疗推进诊所的另一个限制是这种有效的生长因子的广泛影响，使系统的应用有问题。药物输送的一种更牢固的方法可能会限制副作用。另一种方法是了解哪种HSA21基因在小脑中下调了SHH途径的反应，这可能暗示了更多“可吸毒”靶标。我们在两个SHH报告细胞系和斑马鱼胚胎中的100多个HSA21 cDNA的屏幕中鉴定了几个候选基因。将在其他SHH敏感测定中评估Light2测定法中SHH途径激活的基因，以确保它们跨越不同的生物系统及其使用遗传模型确定的特异性（特定目标2）。最后，Davisson的TS65DN小鼠在DS中转化了研究，但是经过20年后，在所有小鼠模型中都存在局限性。我们将通过制作具有稳定集成的HSA21副本的老鼠（特定的AIM 3），以更好的行为和药理测试模型开放新的投资时代。

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Processes and patterns: Insights on cranial covariation from an Apert syndrome mouse model.

过程和模式：对阿佩尔综合征小鼠模型颅骨共变的见解。

DOI：
10.1002/dvdy.498
发表时间：
2022
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
0
作者：
Singh,Nandini;Heuzé,Yann;Holmes,Greg
通讯作者：
Holmes,Greg

What are genes "for" or where are traits "from"? What is the question?